Abstract

Background: This study addresses a key knowledge gap identified by the Institute of Medicine report on quality cancer care. Although there has been a growth in the number of targeted agents approved for the treatment of breast cancer, there are limited data regarding the efficacy, toxicity, and management of side effects in older adults. Neratinib is a potent oral small molecule tyrosine kinase inhibitor. Early clinical data have demonstrated the activity of neratinib in patients who have already progressed through HER2 targeted therapies. This study is designed to evaluate the tolerability and toxicity profile of neratinib in older adults with metastatic breast cancer (MBC) incorporating geriatric oncology design considerations.

Trial Design: This is an open label, single arm, phase II study of single agent neratinib in patients with HER2 positive MBC. Neratinib is given at 240mg orally in 28 day cycles. Unique factors of this geriatric oncology trial design include: 1) pre-treatment and on-treatment geriatric assessment; 2) additional nurse toxicity visits; 3) an algorithm for aggressive management of diarrhea; 4) measurements of the pharmacokinetics (PK) of neratinib; 5) inclusion of biomarkers of aging; 6) measurement of patient adherence; and 7) evaluation of quality of life.

Eligibility Criteria: Patients must be age≥60 with histologically-proven HER2 positive MBC or MBC with HER2 receptor activating mutations. There is no limitation on the number of previous lines of therapy, but patients must have adequate organ and bone marrow functions, and a baseline LVEF ≥ 50%. Exclusion Criteria include: prior treatment with neratinib; major surgery within 28 days; uncontrolled cardiac disease; concurrent use of digoxin; or chronic diarrhea.

Specific Aims: The primary objective of this study is to identify the rate of grade 2 or higher toxicities attributed to neratinib in adult age ≥60 with HER2 over-expressing breast cancer. The secondary objectives are to describe the full toxicity profile (including all grades of gastrointestinal toxicities); to estimate the rate of dose reduction, holds and hospitalizations; to describe the PK parameters; to estimate the adherence rate to neratinib; and to estimate the overall response, clinical benefit rate, progression-free and overall survival. Furthermore, we will explore the role of a cancer-specific geriatric assessment and serum biomarkers of aging (IL-6, CRP, and D-dimer) in predicting treatment toxicities and PK parameters.

Statistical Design: We plan to enroll 40 patients age ≥60 (at least 5 patients age 75 years or older, and no more than 15 patients 60-70) in order to assure that our sample is representative of the entire age range of older adults. Given a sample size of 40 subjects, the widest half-width of the 95% confidence limits for the rate of grade 2 or higher toxicities will be less than or equal to 0.16. An interim analysis will be performed after 20 subjects have been on study for at least one cycle.